The widely used anti-diabetic drug Metformin is able to boost the immune system and increase the potency of vaccines and cancer treatments, says a new study1 published in the June 3 2009 issue of Nature. Researchers at McGill University and the University of Pennsylvania made the discovery that metformin increases the efficiency of the immune system’s T-cells.
After an infection or vaccination, our immune system remembers to keep protecting against the pathogens it has already encountered, with the help of specialized B-cells and T-cells. Immunological memory has long been a fruitful subject of study, but the cellular mechanisms underlying the generation and persistence of long-lived memory T cells remain largely undefined.
“Many genes involved in diabetes regulation also play a role in cancer progression,” explains McGill’s Dr. Russell Jones. “There is also a significant body of data suggesting that diabetics are more prone to certain cancers. However, our study is the first to suggest that by targeting the same metabolic pathways that play a role in diabetes, you can alter how well your immune system functions.”
Metformin is the only anti-diabetic drug that has been proven to protect against the cardiovascular complications of diabetes.2 Metformin activates AMP-activated protein kinase (AMPK), a liver enzyme that plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose and fats3. The AMPK activation is resposible for metformin’s inhibitory effect on the production of glucose by liver cells.
Fatty Acid Metabolism
“We serendipitously discovered that the metabolizing, or burning, of fatty acids by T-cells following the peak of infection is critical to establishing immunological memory,” said Erika Pearce, PhD, of the University of Pennsylvania. “We used metformin, which is known to operate on fatty-acid metabolism, to enhance this process, and have shown experimentally in mice that metformin increases T-cell memory as well as the ensuing protective immunity of an experimental anti-cancer vaccine.”
Recent research has revealed common links between diabetes and cancer, such as how metabolic pathways, the basic chemical reactions that happen in our cells, are controlled in both diseases. These findings point to a new link between the metabolic pathways deregulated in cancer and diabetes, and their role in immune cell function. The results suggest that common diabetic therapies which alter cellular metabolism may enhance T-cell memory, providing a boost to the immune system. This could lead to novel strategies for vaccine and anti-cancer therapies.
Researchers used mice deficient in TRAF6, which is a protein important to immune response. They found that CD8 T-cells deficient in TRAF6 have an initial response, in that they are able to propagate into an army of “effector cells” that can clear infection. But TRAF6-deficient CD8 T cells do not become memory cells that can recall a particular infectious agent when the body encounters it a second time.
The team then used microarray analysis to compare the gene expression profiles of TRAF6-deficient cells and cells with TRAF6. “We discovered differences in genes that regulate fatty acid metabolism,” says Pearce. Fatty acids are broken down to produce energy; microarray analyses revealed that TRAF6-deficient CD8 T cells exhibit altered expression of genes that regulate that process.
Giving the mutant mice Metformin restored their fatty acid oxidation and generation of memory cells that lack TRAF6. Metformin surprisingly also increased the generation of immune memory cells in “normal” mice, and consequently was able to considerably improve the efficacy of an experimental anti-cancer vaccine. Lack of fatty acid metabolism is correlated with lack of T-cell memory and through in vitro studies the team also saw that T cells burn more fatty acids when given metformin.
T-cells that are forming an army of effector cells burn glucose for their energy, but non-proliferating T cells, such as memory cells, burn fatty acids and glucose interchangeably in a different metabolic pathway. From this, Pearce explained, “it is implied that there’s a switch in metabolism somewhere along the way between proliferating and non-proliferating T cell populations.” Perhaps at the peak of the proliferation, when energy is limiting and cells are metabolically stressed, there is a switch to another energy pathway to survive, say from glucose to fatty acids.
1. Enhancing CD8 T-cell memory by modulating fatty acid metabolism Erika L. Pearce et. al- Nature advance online publication 3 June 2009 | doi:10.1038/nature08097 2. Selvin E, Bolen S, Yeh HC, et al. (October 2008). “Cardiovascular outcomes in trials of oral diabetes medications: a systematic review”. Arch Intern Med 168 (19): 2070–80 3. Towler MC, Hardie DG (2007). “AMP-activated protein kinase in metabolic control and insulin signaling”. Circ Res 100 (3): 328–41.